tbuckley/cabot-search huggingface dataset:
Association of Omicron vs Wild-type SARS-CoV-2 Variants With Hospital-Onset SARS-CoV-2 Infections in a US Regional Hospital System
Authors: Michael Klompas, Michael C. Pandolfi, Ansa B. Nisar, Meghan A. Baker, Chanu Rhee
Journal: JAMA (2022)

Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave
Abstract 3108: Preclinical studies of chemotherapies and targeted therapies to address gastric cancer disparities
Authors: Hongyong Zhang, Ana Patricia Estrada-Florez, Paul Lott, Ted William Toal, Alexa Morales-Arana, Alma Poceros-Coba, Ai-Hong Ma, Nicole Britney Halmai, Luis Carvajal-Carmona
Journal: Cancer Research (2022)

Abstract Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, and its prognosis remains poor because most tumors were detected in late stages and the 5-year survival is less than 5%. The Cancer Genome Atlas (TCGA) study found that 70% of all GCs have mutations that can be targeted with existing drugs, yet only four molecularly-guided therapies have been approved. GCs have strong disparities in incidence, mortality and survival that disproportionately affect different populations of color. No large-scale cancer genomic research has been carried out in U.S. minority populations. GC molecular data from U.S. minority residents is crucial to improve outcomes, as genomic phenotypes have been associated with differential prognosis and response to treatments. To our knowledge, minority patient-derived models have not been used to test GC therapies. In this study, several organoids lines from minority patients were established and used as an in vitro platform for screening effective therapies. After genomic data analyses, six minority patient-derived organoids with or without cell cycle regulator or PI3K/AKT/mTOR pathway gene alterations were tested for responses to first-line therapies, targeted drugs and combination treatments. Among the 24 PDX models established, the efficacy study of PDX model PDX015 which has amplifications of CDK and AKT genes showed the targeting therapy (a CDKi) can effectively prolong overall survival of mice bearing xenograft treated with the CDKi (60 days), compared with those mice in control group (22 days). In addition, an AKT inhibitor was found significantly inhibited tumor growth in CDKi-resistant mice treated with the CDKi/AKTi combination. In conclusion, investigating the efficacy of targeted therapies in these U.S. minorities will empower precision medicine applications in GC patients and improve GC treatment outcomes. Minority-patient derived tumor models have great potential in preclinical studies of chemotherapies and targeted therapies to address gastric cancer disparities. Citation Format: Hongyong Zhang, Ana Patricia Estrada-Florez, Paul Lott, Ted William Toal, Alexa Morales-Arana, Alma Poceros-Coba, UCaMP Consortium, Ai-Hong Ma, Nicole Britney Halmai, Luis Carvajal-Carmona. Preclinical studies of chemotherapies and targeted therapies to address gastric cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3108.
Abstract 6167: Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth
Authors: Patrick Jonker, Alexander Muir
Journal: Cancer Research (2022)

Abstract Both the cell-intrinsic metabolic network and the uniquely altered cell-extrinsic tumor microenvironment dictate tumor metabolism. However, while much is known about how cell-intrinsic factors regulate tumor metabolism, the effects of cell-extrinsic factors remain poorly understood. In particular, despite evidence that tumor nutrient availability extrinsically regulates tumor metabolism, further investigation has been hindered by the lack of models to study physiological nutrient availability in vitro.To accurately model the tumor nutrient microenvironment, our group quantified nutrient availability in pancreatic ductal adenocarcinoma (PDAC) tumor perfusate and created a medium to mimic this in vitro, called tumor interstitial fluid medium (TIFM). We compare the effects of TIFM-culture to maintenance in conventional culture medium (RPMI-1640) as a control for standard laboratory conditions. Using this model, I found that TIFM-cultured PDAC cells downregulate lipid synthesis, making TIFM-cultured cells uniquely reliant upon extracellular lipid uptake for growth. Analysis of murine PDAC tumors confirms downregulated lipogenesis in vivo, suggesting cell-extrinsic nutrients render lipogenesis dispensable—and lipid uptake necessary—for PDAC tumor growth. Notably, this contrasts studies in conventional culture media that claim lipogenesis is critical for PDAC growth.I am currently working to: (1) understand how the nutrient microenvironment alters lipid metabolism and (2) determine the extracellular lipids and transporters pancreatic cancer cells require for growth. Regarding the first question, transcriptomic analysis of TIFM-cultured cells revealed significant deactivation of SREBPs, master regulators of intracellular lipid and sterol synthesis, suggesting cell-extrinsic nutrient cues suppress lipogenesis by altering SREBP signaling. I am currently investigating which TIFM nutrients alter this signaling. I am also performing lipidomics analysis and lipid transporter knockdown experiments to identify lipids and transporters that TIFM-cultured cells require for growth. Collectively, these experiments will clarify the role extracellular nutrients play in driving changes to PDAC lipid metabolism and may suggest novel therapeutic treatment options for PDAC patients. Citation Format: Patrick Jonker, Alexander Muir. Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6167.
Abstract 1431: ADO contributes to tumour initiating phenotypes
Authors: Sandy Che-Eun Serena Lee, Andrea Hye An Pyo, Marianne Koritzinsky
Journal: Cancer Research (2022)

Abstract 2-aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that plays a role in both metabolism and protein stability. ADO directly metabolizes cysteamine to produce hypotaurine and taurine in mammals. ADO has also been recently identified to promote oxygen dependent stability of a subset of substrates involved in the N-degron pathway in mammals (IL32, RGS4 and RGS5). The ability of ADO to target protein stability of signaling molecules suggests that it may have the potential to transduce rapid responses to hypoxia and affect tumour initiation and progression phenotypes. Here, we have successfully knocked down and knocked out ADO using two independent siRNAs and clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) system, respectively. We have assessed proliferation and migration through the Incucyte® ZOOM system by imaging cell confluency over time. Survival was assessed through a clonogenic assay. siRNA mediated knockdown of ADO in cervical (HeLa and SiHa), pancreatic (Panc1 and Capan2) and liver (SNU499 and Huh6) cancer cell lines drastically reduced proliferation, survival, and migration in normoxia. These results were also replicated in hypoxia (0.2% O2) across all 6 cell lines. Out of the 6 cell lines, the liver cancer cell lines were most drastically affected by the knockdown of ADO. This phenotype was replicated in the ADO KO cell lines. Taken together, these data suggest that expression of ADO may contribute to phenotypes that induce aggressive tumour phenotypes by targeting the stability of specific proteins and altering cellular metabolism in mammals. Citation Format: Sandy Che-Eun Serena Lee, Andrea Hye An Pyo, Marianne Koritzinsky. ADO contributes to tumour initiating phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1431.
Abstract 1624: Immune cell killing assay for measuring the effects of immunomodulating agents in lung cancer cells <i>in vitro</i>
Authors: Jenni H. Mäki-Jouppila, Jukka P. Rissanen, Katja M. Fagerlund
Journal: Cancer Research (2022)

Abstract Direct effects of cancer therapeutics on immune cell activity can be challenging to determine on system level in vivo. Therefore, it is important to develop and discover novel ways to study the effects of immune cells on cancer cells using also in vitro assays. Our aim was to validate an in vitro immune cell killing assay where activated peripheral blood mononuclear cells (PBMCs) target lung cancer cells and induce apoptosis. A549 human lung carcinoma cells (ATCC) were used as target cells in the co-culture and were plated into 96-well plates. 24 hours later, human PBMCs (Lonza) were added to the culture as effector cells and activated with anti-CD3 and IL2. Apoptosis was detected using IncuCyte Annexin V reagent, which was added to the cells at the same time with immune cell activators. Cell proliferation was monitored with a live cell imager IncuCyte S3 (Sartorius) for three to four days before terminating the cultures. Cell viability was determined by CellTiter Glo (Promega) at the end of the study. Treatment of cells with anti-CD3 was able to activate immune cells alone but the effects were observed with lower test concentrations in combination with IL-2. Therefore, IL-2 potentiates the effect of anti-CD3 on immune cell activation and decreases cancer cell viability in co-culture. The immune cell killing assay based on live cell imaging can be used for studying the effects of immunomodulating agents on cancer cell viability and to evaluate the activity of immune cells in the presence of therapeutics. Citation Format: Jenni H. Mäki-Jouppila, Jukka P. Rissanen, Katja M. Fagerlund. Immune cell killing assay for measuring the effects of immunomodulating agents in lung cancer cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1624.
Abstract 1317: The role of PAX8 in copy number-high uterine cancers: Inflammatory cytokine modulation
Authors: Lauren Karnolt, Maja Okuka, Susan Read, Yongchao Dou, Bing Zhang, Thomas J. Rutherford, Matthew L. Anderson
Journal: Cancer Research (2022)

Abstract Paired Box 8 (PAX8) is a transcription factor clinically utilized as a histologic biomarker for cancers arising in tissues derived from the embryonic Mullerian tract. Although dysregulated PAX8 expression has recently been shown to promote the growth of ovarian and renal cancers, its role in uterine cancer remains poorly understood. Here, we hypothesized that overexpression of PAX8 promotes uterine cancer growth and metastasis. When 108 uterine cancer specimens were evaluated by mass spectroscopy, the highest levels of PAX8 were found in TP53-mutated, copy number (CN)-high specimens. In vitro, we found that targeting PAX8 expression resulted in decreased rates of both proliferation and apoptosis in multiple representative cell lines (ARK2 and ARK4). PAX8 knockdown also negatively impacted rates of in vitro migration and invasion assessed using commercially available Boyden chamber assays. Using whole-exome and transcriptomic profiling performed by Next Generation Sequencing, we found that PAX8 knockdown resulted in increased expression of 268 gene products by &amp;gt;1.5-fold, and decreased expression of 179 gene products (adj p&amp;lt;0.01; FDR&amp;lt;1%). Specific gene products whose expression was altered by targeting PAX8 expression included IL-1β, IL-11, and MUC1. With qPCR, we confirmed that levels of IL-1β were 13.8-fold and 3.4-fold higher in cultures of ARK2 and ARK4 cells transfected with PAX8-specific siRNA, respectively, when compared to cultures transfected with a nontargeting control (p&amp;lt;0.01). Using these transfections, we also confirmed increased expression of IL-11 in ARK2 cells (RQ=3.22, p&amp;lt;0.01) and ARK4 cells (RQ = 2.28, p&amp;lt;0.01), and increased expression of MUC1 in ARK2 cells (RQ=1.13, p&amp;lt;0.01). Collectively, our findings demonstrate that PAX8 regulates the proliferation of CN-high uterine cancers, potentially through the regulation of IL-1β expression. Notably, our data also implicates PAX8 expression as a key mediator of the inflammatory response to these aggressive cancers. Key differences in PAX8’s relationship with proliferation and these select few signaling molecules, compared to what is seen in other PAX8-dependent cancers, suggest unique roles for PAX8 as an oncogene in uterine cancers. Citation Format: Lauren Karnolt, Maja Okuka, Susan Read, Yongchao Dou, Bing Zhang, Thomas J. Rutherford, Matthew L. Anderson. The role of PAX8 in copy number-high uterine cancers: Inflammatory cytokine modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1317.
Abstract SY24-01: Changes in adaptive landscapes and somatic evolution as we age
Authors: James V. DeGregori
Journal: Cancer Research (2022)

Abstract Why do we get cancer? Why is cancer highly associated with old age, and why are insults like smoking, obesity, and sunlight associated with increased risk of cancers? Of course, these contexts all cause mutations, and some of these mutations can contribute to malignant phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are microenvironmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, somatic evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We will discuss the evidence from many labs for microenvironmental change driven selection in the evolution of cancer, additional support from epidemiological and clinical studies, as well as the limitations, inconsistencies and unknowns that require the attention of cancer researchers. My own lab has been using mouse models of cancer initiation, mathematical models of clonal evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. Using Monte Carlo modeling, we have explored the impact of key somatic evolutionary parameters on multi-stage carcinogenesis, revealing that two additional major mechanisms, aging-dependent somatic selection and life history-dependent evolution of species-specific tumor suppressor mechanisms, need to be incorporated into the multi-stage model of carcinogenesis to make it capable of generalizing cancer incidence across tissues and species. Using mouse models, we have shown that aging and inflammation dependent changes in tissue microenvironments dramatically impact the fitness impact of oncogenic mutations, leading to aging and inflammation driven clonal expansions in the hematopoietic compartment. These studies have also uncovered molecular mechanisms underlying oncogene-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. While we largely cannot prevent mutation accumulation through our lives, we do have the ability to manipulate tissue microenvironments so as to change the evolutionary trajectories of oncogenically-mutated cells. Citation Format: James V. DeGregori. Changes in adaptive landscapes and somatic evolution as we age [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY24-01.
Abstract 3866: Spatial multi-omics analysis targeting protein and RNA biomarkers on a single FFPE tissue section using an integrated staining workflow
Authors: Gourab Chatterjee, Grace E. Vezeau, Milena D. Lazova, Michael Sismour, Mael Manesse
Journal: Cancer Research (2022)

Abstract Biomarker detection approaches capable of rapid identification, quantification, and spatial mapping of many cellular sub-types of the tumor environment in FFPE tissue sections are becoming increasingly valuable for investigating the highly complex biology of tumors and their respective microenvironments. Multiplexed immunofluorescence (mIF) enables simultaneous identification of multiple protein targets within their spatial context in FFPE tissues, thereby facilitating more in-depth analysis including cellular phenotyping. In parallel, spatial transcriptomic analysis can provide additional insights into cellular function. Multi-omics analyses combining protein and nucleic acid biomarkers on a single tissue section can provide a deeper understanding of the complex cellular interactions in the context of the tumor. In this study, we demonstrate the versatility of Ultivue InSituPlex technology (ISP) through an integrated workflow for co-detection of protein and RNA on a single tissue section. FFPE tumor tissue samples were processed for protein and/or RNA detection on a single slide with an integrated workflow using ISP. Briefly, slides were stained for both protein and RNA targets using a Leica Biosystems BOND RX autostainer. Post-staining, the slides were imaged on ZEISS Axioscan.Z1 in five different fluorescent channels and evaluated using IndicaLabs HALO analysis software. In parallel, control serial sections were stained to perform comparative analyses. Here we report an efficient and streamlined integrated workflow for co-detection of protein and RNA on a single section, powered by ISP technology. The protein and RNA targets were detected both sequentially (over different imaging rounds) with increased multiplexing capabilities, as well as concurrently (in the same imaging round) for a higher throughput solution, thereby demonstrating the flexibility of the workflow. Comparative analyses between the different workflows confirmed minimal effect on staining performance of individual biomarkers (both protein and RNA). The gentle treatment of FFPE tissue sections through ISP technology preserves tissue integrity, and morphology enabling efficient detection of protein and RNA targets on a single section. The integrated workflows presented here demonstrate compatibility of the individual steps in the assay towards co-detection of protein and RNA targets with efficient sensitivity in terms of staining performance for individual biomarkers. Citation Format: Gourab Chatterjee, Grace E. Vezeau, Milena D. Lazova, Michael Sismour, Mael Manesse. Spatial multi-omics analysis targeting protein and RNA biomarkers on a single FFPE tissue section using an integrated staining workflow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3866.
Abstract 2559: Tumor lipogenesis influences macrophage polarization in advanced prostate cancer
Authors: Shannalee R. Martinez, Carla Barrientos Risso, Ralphdy Vergne, Nathan R. Wall, Julie Dutil, Carlos A. Casiano, Gilberto Ruiz-Deya, Carlos Joel Diaz Osterman
Journal: Cancer Research (2022)

Abstract Aberrant lipid metabolism in prostate tumors is linked to aggressive disease and poor outcomes. The purpose of this study was to identify mechanisms by which lipid metabolism in prostate cancer cells influences the tumor immune microenvironment, with emphasis on the activation of macrophages. Our hypothesis that fatty acid synthase-driven de novo lipogenesis promotes immune evasion via alternative M2-like macrophage activation was tested using human monocyte (U937)-derived macrophages co-cultured with prostate cancer cells in the presence of fatty acid synthase inhibitors. Monocytes were differentiated to macrophages in vitro using phorbol-12-myristate-13-acetate for 48 hours prior to co-culture with prostate cancer cells. Macrophage polarization following co-culture with prostate cancer cells was evaluated using multi-parameter flow cytometry to detect established M1 (CD80, CD86) and M2 (CD163, CD206) markers. Furthermore, the expression of fatty acid synthase and pan-macrophage marker CD68 in human prostate tumor tissue microarrays was evaluated using multiplex immunohistochemistry. The lipogenic enzyme and macrophage staining correlated with disease progression, reaching peak levels in metastatic tissues. These findings indicate that tumoral fatty acid synthase is an important mediator of tumor-immune crosstalk, particularly in the context of aggressive and metastatic prostate cancer. These data further suggest that fatty acid synthesis represents a targetable complement to immune-enhancing therapies by modulating tumor cell metabolism, underscoring the need for further evaluation of agents targeting lipid metabolism in prostate cancer. Citation Format: Shannalee R. Martinez, Carla Barrientos Risso, Ralphdy Vergne, Nathan R. Wall, Julie Dutil, Carlos A. Casiano, Gilberto Ruiz-Deya, Carlos Joel Diaz Osterman. Tumor lipogenesis influences macrophage polarization in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2559.